CN1161606C - 带有含离子选通通道的类脂膜的生物传感器 - Google Patents
带有含离子选通通道的类脂膜的生物传感器 Download PDFInfo
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Abstract
一种生物传感器,带有含选通离子通道的类脂膜(7),所述通道对使用中涂敷于类酯膜(7)第一面上的样品中分析物分子存在与否敏感。该类脂膜(7)被置于一对电极(1,2)之间,其中,第一多孔凝胶层(4)被涂到类脂膜(7)的第一面。
Description
本发明涉及一种生物传感器,具体地讲,是涉及一种通过检测或测量离子跨越类脂膜迁移而起作用的那种类型的生物传感器。
基于使用跨越双层膜的选通通道蛋白质的生物传感器是相当有价值的。每一个单独结合作用,在一个实际的测量间隔中,可以引发多达109个单个离子通过该通道。此外,不同通道的作用基本上是独立的,并且通过这些通道的离子流以线性形式合并。这两个因素激发人们对于感知显示出极佳敏感度和很高动态范围的生物分子一般原则的希望。
为了达到高动态范围,必须选择在目标生物分子存在时是打开的通道蛋白质。对于许多天然存在的通道蛋白质(典型的例子是神经细胞中的神经传递质受体)就是这种情况。按照一种更为常见的适合的方式,一些坚固的闭塞通道,具体讲,如短杆菌肽,按照一种通常使通道闭塞的方式与抗体分子化学键合,而当抗原键合时则不阻塞。
通过这些通道蛋白质传递的电荷实际上由溶剂化物离子组成。为了能够进行进一步处理,必须将这些离子与通过位于双分子层膜前后两面的电极上的导线传递的电子流进行交换。按照一种已知的方式,双分子层膜的位置直接紧邻背面贵金属电极。离子朝何处流并不清楚。如果它们在电极上放电,相关的化学变化将不可避免的导致降解。
按照另一种已知的方式,在双分子层膜的后面存在包含在凝胶中的电解质。所述的双分子层膜是利用标准技术横过毗邻凝胶的孔安装的。凝胶对双分子层膜提供一定程度的实体支撑,结果使得它能够耐受测试液体的相当强烈的搅动。然而,所述的双分子层膜不能脱水,必须在待测水质介质中进行测量之前即时制作。它直接暴露于介质中,经不起与固体的接触。
目前业已设计出一种以对穿过类脂膜传递的离子进行测量为基础的新颖生物传感器,这种类脂膜可以克服或基本上减轻已知类型的这种传感器的缺点。
根据本发明的第一个方面,生物传感器包括置于一对电极之间的膜,其中类脂膜的第一面涂敷第一多孔凝胶层,而该类脂膜的第二面涂敷第二多孔凝胶层;并且类脂膜含有选通离子通道,所述选通离子通道对使用时通过所述凝胶层而涂敷于所述类脂膜第一面上的样品中分析物分子的存在与否敏感。
根据本发明的生物传感器,其优点主要在于涂到类脂膜上的第一多孔凝胶层保护该类脂膜不脱水和免受机械接触所造成的物理损伤。并且仍然可以允许包含在样品中的分子通过类脂膜。由于类脂膜不会由于生物传感器的干燥而损坏,所以生物传感器可以在干燥的状态下进行包装和储存,可以在使用前即时再水合。
最好还将第二凝胶层加到所述的类脂膜的第二面以便于进一步保护类脂膜,并且提供与毗邻电极的必须的隔离,以及容纳一个该电极所需要的离子贮存器。
凝胶最好是具有生物相容性和多孔性凝胶,最为可取的是水凝胶。适合的凝胶材料包括琼脂、葡聚糖、角叉菜胶、藻酸、淀粉、纤维素或这些材料的衍生物,例如羧甲基衍生物或聚乙烯醇、聚丙烯酸、聚丙烯酰胺或聚乙二醇等水溶胀性有机聚合物。特别可取的是琼脂。被认为特别优选的其他凝胶材料包括聚丙烯酰胺凝胶。
具体第一凝胶层的厚度优选有允许在适当短的时间内,例如短于5分钟,更优选短于2分钟内使大约1KD的生物分子扩散之厚度。第一和第二凝胶层的厚度最好小于5mm,例如0.1至2mm,最为优选大约1mm。
类脂膜最好是两亲分子的双层,最为可取是一种或多种磷脂,例如磷脂酰胆碱和/或磷脂酰乙醇胺的双分子层膜。类脂化合物可以具有链长为C12-C22,最优选C12-C18的烃基链端。一种特别优选的磷脂是二油酰磷脂酰胆碱。可以使用的其他成膜分子包括两亲聚合物,例如带有亲水侧基的疏水聚合物链。这样的聚合物的一个例子是具有磷脂酰胆碱侧基的聚硅氧烷。
限定选通离子通道的适合的分子被掺入所述的类脂膜,例如与膜结合的蛋白质。
最好将一种钻孔的惰性的和不渗透的材料片置于类脂膜和第二凝胶层之间。适合的这种材料是聚四氟乙烯。这种材料片优选很薄,例如厚度小于大约100μm,更优选厚度为10μm。该片最好有一个或多个直径10至200μm,更优选大约50至100μm的孔。该材料片只允许电极间的电流在片的孔区域流动。
类脂膜可以通过以下方式形成,将成膜类脂和限定选通离子通道的分子溶解到一种溶剂中,并将所形成的溶液涂敷到第二凝胶层(或邻接第二凝胶层的钻孔惰性材料片)上。可以使用任意适合的溶剂,只要其基本上不与水混溶即可。优选可以引发氢键的极性溶剂,这是因为使用它们为溶液完全覆盖表面提供了很强的驱动力。特别可取的溶剂是氯仿。该溶液的浓度最好为0.01至5%w/v,更优选小于1%w/v,例如大约为0.2%w/v。
然而,上述形成类脂膜的方法并不总是合适的。例如,氯仿可能会使某些配位体-选通通道蛋白质变性。一种适合这种情况的用于形成类脂膜的其它方法,涉及形成含有成膜类脂和限定选通离子通道的分子的逆胶束溶液或乳液。胶束溶液或乳液有烃连续相。所述烃优选烷烃,最优选己烷。
可用于前述段落中所描述过的其它方法的一官能配位体-选通通道蛋白质是尼古丁乙酰胆碱受体(the nicotinicacetycholinereceptor)(nAChR-见G Puu et al,Biosens.Bioelectron.10(1995),463)。这种神经受体具有许多稍有变化的变体,在大多数具有神经系统的动物体中都可以找到,在普通的波鳐类石斑电鳗电器官中可以获得极为丰富的来源。通过均化所述鳐鱼的电器官并按照CsCl梯度离心分离以分离出膜键合馏分形成的粗提取物具有基本上水质的连续相。通过降低水的比例,可以使乳液反相并由此制备出具有形成类脂膜所需特性的烃连续相反相乳液。
电极最好是具有常规形式的贵金属电极。最优选的电极是在合适基底,例如云母,片上形成的银/氯化银电极。类脂膜的第一面上的电极最好具有一个用做样品引入口的孔。如果装置包括以上所述打孔材料片时,电极孔最好对准片上的(一个或多个)孔。
本发明还包括对样品中的被分析物分子进行定性或定量测定的方法,该方法包括将样品涂敷到根据本发明的第一个方面的生物传感器中的多孔凝胶的第一层上。
最优选本发明生物传感器按照以下方式装配起来,包括将两个平面电极的每一个涂一层多孔凝胶层、将类脂溶液置于所述凝胶层之一上以形成类脂膜,然后将一个电极置于另一个电极的顶部,使得类脂膜位于两个电极之间并且与凝胶层接触。通常,生物传感器是在使类脂膜能自发形成的条件下组装起来的。单层类脂将形成在溶液或乳液与相应的胶层之间的界面上。由于大量的溶液或乳液从胶层之间排放或蒸发,两个单层合起来形成类脂膜双层。
以下参考附图仅以举例的方式对本发明的一个优选实施方案作更为详细的说明,其中
图1是本发明生物传感器电池的示意剖面侧视图;
图2显示使用图1所示类型的电池测得的电池电阻(对数电阻标度)的条形直方图,分别表示带有或没有类脂双层的情况;
图3显示长时间暴露于短杆菌肽之后,使用图1的电池所测得的电池电阻(对数标度)值对电阻达极限值所需时间作图所得的分散图。
首先参考图1,根据本发明的生物传感器电池形成在以下所述的云母基底1a,2a上的平面银/氯化银电极对1,2之间。上部的云母基底1a有一个试验样品可以从中穿过引入的直径3mm的孔3。电极1,2之间的空间填充有第一和第二琼脂糖凝胶层4,5(按下面所述配制),其间由10μm厚PTFE片6隔开,该片上表面形成类脂双分子层膜7。PTFE片6有至少一个孔10。银电线8,9与电极1,2相连接。凝胶片的形成
将按重量计1%的琼脂糖、10%的丙三醇、0.1M NaCl、0.1M KCl和0.01M CaCl2以及其余为超纯水的混合物加热到沸点。在还是液体的时候将混合物吸到亲水玻璃模具中或表面上(一般为6ml)并使之凝固。
凝胶片4、5在形成之初,厚1mm。使它们在薄层流动的环境空气(标称23℃,50%相对湿度)中完全脱水。用电解质溶液(纯水中的0.1M NaCl、0.1M KCl和0.01M CaCl2)再水合后凝胶从其基底上被取出。
电极的形成
按以下描述制备银/氯化银电极1,2。将新切割的云母片1a,2a按需要(通常尺寸几厘米片上孔径为3mm)打孔。将它们分别用氯仿和甲醇漂洗和超声波处理。将直径12.5μm的银线8,9放在表面上,而后将表面涂敷银石墨粉并使之干燥,使银线8,9固定。在9V电压下使用不锈钢反电极在1M的HCl中使表面电解氯化,一开始作为阳极进行10秒钟,而后作为阴极进行另外10秒。将前面段落描述过的再水合凝胶层4,5放上与银面接触。生物传感器的组装
将10μm厚的PTFE膜切割成厘米尺寸的小片并用红热的钨尖针打孔,形成的孔径一般为50-100μm。
涂敷溶液由氯仿中浓度为20g/l的L,α-二油酰基磷脂酰胆碱构成。
图1所示的结构按照以下所述组装。将打孔的PTFE片6放在有凝胶涂层5的下电极2上。将10μl涂敷溶液涂布在PTFE片6上,将有凝胶涂层4的第二打孔电极1放在顶部,保证孔3对准PTFE片6中的孔。
测量
为了进行测量,将按以上程序制造的电解质双层电池放入电屏蔽盒中,将一滴试验溶液放在云母孔上。利用Keithley Model 175数字万用表测量电池的电阻。为了测量电流随时间的变化,使用具有1.0GΩ互阻抗的Bio-Logie BLM-120双膜放大器将电池电流转化为电压。输出电压用Cambridge Electronic Design1401 Plus多通道分析仪数字化处理并由以CDR程序运行的计算机记录。
图2表示如上所述制备的电池电阻的六次测量结果,与无类脂膜的情况下所作测量进行比较。可以看出,类脂膜的作用是显著地提高了测量电阻。
图3表示在长时间暴露于1g/l的短杆菌肽-D溶液之后,如上所述制备的电池测得的的电阻值。这种蛋白质的作用是降低电池电阻。
Claims (9)
1.一种生物传感器,该生物传感器包括置于一对电极之间的类脂膜,其中类脂膜的第一面涂敷第一多孔凝胶层,而该类脂膜的第二面涂敷第二多孔凝胶层;并且类脂膜含有选通离子通道,所述选通离子通道对使用时通过所述凝胶层而涂敷于所述类脂膜第一面上的样品中分析物分子的存在与否敏感。
2.根据权利要求1所述的生物传感器,其中凝胶是水凝胶。
3.根据权利要求1所述的生物传感器,其中第一凝胶层要使得大约1KD的生物分子在短于5分钟的时间出现扩散。
4.根据前述权利要求任意一项所述的生物传感器,其中类脂膜的类脂化合物有链长为C12-C22的烃基链端。
5.组装生物传感器的方法,该方法包括将两个平面电极的每一个涂一层多孔凝胶层、将类脂溶液置于所述凝胶层之一上以形成类脂膜,然后将一个电极置于另一个电极的顶部,使得类脂膜位于两个电极之间并且与凝胶层接触。
6.根据权利要求5所述的方法,其中类脂膜形成之前,将成膜类脂和限定选通离子通道的分子溶解到溶剂中。
7.根据权利要求6所述的方法,其中所述溶剂是氯仿。
8.根据权利要求5所述的方法,其中类脂膜形成之前,将成膜类脂和限定选通离子通道的分子掺入具有富烷烃连续相的逆乳液中。
9.根据权利要求8所述的方法,其中烷烃是己烷。
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1998
- 1998-06-15 DK DK98929560T patent/DK0988533T3/da active
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- 1998-06-15 ES ES98929560T patent/ES2193535T3/es not_active Expired - Lifetime
- 1998-06-15 US US09/445,817 patent/US6177000B1/en not_active Expired - Fee Related
- 1998-06-15 DE DE69811886T patent/DE69811886T2/de not_active Expired - Fee Related
- 1998-06-15 JP JP50395799A patent/JP2002505007A/ja not_active Ceased
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- 1998-06-15 AU AU79266/98A patent/AU726398B2/en not_active Ceased
- 1998-06-15 NZ NZ501640A patent/NZ501640A/en unknown
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CA2293284A1 (en) | 1998-12-23 |
GB9712386D0 (en) | 1997-08-13 |
EP0988533B1 (en) | 2003-03-05 |
ES2193535T3 (es) | 2003-11-01 |
CN1301343A (zh) | 2001-06-27 |
NZ501640A (en) | 2001-11-30 |
HK1027623A1 (en) | 2001-01-19 |
DE69811886D1 (de) | 2003-04-10 |
AU7926698A (en) | 1999-01-04 |
EP0988533A1 (en) | 2000-03-29 |
DK0988533T3 (da) | 2003-07-07 |
KR100550404B1 (ko) | 2006-02-09 |
DE69811886T2 (de) | 2004-03-04 |
KR20010013583A (ko) | 2001-02-26 |
ATE233897T1 (de) | 2003-03-15 |
JP2002505007A (ja) | 2002-02-12 |
PT988533E (pt) | 2003-06-30 |
US6177000B1 (en) | 2001-01-23 |
WO1998058248A1 (en) | 1998-12-23 |
AU726398B2 (en) | 2000-11-09 |
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